(Revised Abstract) DESCRIPTION (provided by applicant): The E. Coli Heat-Stable Enterotoxin STh(1-19) is a member of the guanylin uroguanylin/ST family of peptides, which regulates net chloride and fluid secretion within the intestinal track. This effect on fluid secretion has been shown to be mediated by the guanylate cyclase-C receptor (GC-C), which is highly expressed on the apical surfaces of intestinal epithelia. The high affinity of STh(1-19) for the GC-C receptor, coupled with the high degree of in vivo stability of the molecule, has made it a promising vector for targeting diagnostic and/or therapeutic radionuclides to tumors expressing GC-C. Recent findings have indicated that a novel and distinct STh(1-19) binding protein (SThBP) is highly expressed on various human tumor cell types, including human pancreatic and breast cell lines. Binding of STh(1-19) to STh-BP does not elicit the production of cGMP, a hallmark of STh(1-19) binding to GC-C. Additionally, GC-C and STh(1-19) binding to STh-BP expressed on cell lines derived from human adenocarcinomas of pancreas and breast are in the low nanomolar range, comparable to STh(1-19) binding affinity to GC-C. As with the STh(1-19)/GC-C binding interaction, binding of STh(1-19) to cancer cells expressing STh-BP can result in internalization of labeled molecules within the cell, an important factor in increasing tumor/nontarget tissue ratios. Combined, these observations suggest that radiolabeled STh(1-19) analogs could be promising targeting vehicles for the imaging and treatment of human pancreatic and breast cancers. Accordingly, the specific aims of this application are designed I) to characterize the molecular identify of STh-BP; ii) to determine the tissue distribution of STh-BP in epithelial cells isolated from normal and malignant breast tissue obtained from the Human Cancer Tumor Bank Core facility; iii) to synthesize radiolabeled STh(1-19) analogs which can be used as targeted SPECT imaging agents; and iv) to test the performance of these analogs both in vitro and in vivo. Accomplishment of these goals will significantly increase our knowledge of a promising new target for the imaging and treatment of human cancer, and provide a platform from which our long-term objectives of cancer treatment can be explored.